The determinants of the relationship of the dose of furosemide to its effect are poorly defined. By studying the relationship in normal subjects of natriuresis and diuresis to the concentration of furosemide in different biologic fluids (serum, urine), we hope to define a clear relationship between dose, concentration of the drug in a body compartment, and drug effect. Because furosemide has an intraluminal site of action, we predict urine concentrations or amounts of furosemide will correlate with effect. After defining these relationships in normals, we propose a logical extension to similar studies in different disease states and therapeutic settings. By studying patients with various degrees of uremia and subjects receiving other agents which affect delivery of furosemide to its active site (probenecid, indomethacin), we can assess the role of modulators of the amount of furosemide reaching its site of action and diuretic effect. By studying patients with disease states associated with changes in delivery of sodium to the loop of Henle and with hemodynamic changes (congestive heart failure and renal transplant recipients), we hope to assess determinants of furosemide's effects other than and in addition to changes in delivery of the diuretic to its site of action. By comparing the effect of probenecid to that of indomethacin on the diuretic effects of furosemide, we hope to more clearly differentiate the importance of pharmacokinetic interactions with these drugs from effects on possible mediators of the diuretic effects of furosemide.